Comparative Efficacy and Acceptability of Endoscopic Methods for Rectal Neuroendocrine Neoplasms with Low Malignant Potential: A Network Meta-analysis

Background/Aims: Although endoscopic resection is an effective treatment of rectal neuroendocrine neoplasms (R-NENs) with low malignant potential, there is no consensus on the most recommended endoscopic method. This study aimed to assess the efficacy and acceptability of different endoscopic treatments for R-NENs with low malignant potential. Materials and Methods: We searched databases for studies on treatments of R-NENs using endoscopic resection. These studies comprised techniques such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), modified endoscopic mucosal resection (EMRM), modified endoscopic submucosal dissection (ESDM), and transanal endoscopic microsurgery (TEM). The primary outcomes assessed were histological complete resection (HCR). Results: Overall, 38 retrospective studies (3040 R-NENs) were identified. Endoscopic mucosal resection with a cap (EMRC), endoscopic mucosal resection with ligation (EMRL), ESD, ESDM, and TEM demonstrated higher resectability than did EMR in achieving HCR. Endoscopic mucosal resection, EMRC, EMRL, EMRP, EMRD, and EMRU required shorter operation times than did ESD. Endoscopic mucosal resection, EMRC, ESDM, and TEM incurred lower risks than did ESD. Conclusion: Regarding R-NENs ≤20 mm with low malignant potential, ESD could be used as the primary treatment. However, TEM may be more effective if supported by economic conditions and hospital facility. With respect to R-NENs ≤16 mm with low malignant potential, EMRL could be used as the primary treatment. In regard to R-NENs ≤10 mm with low malignant potential, EMRL, EMRC, and ESD could be used as the primary treatment. However, EMRL and EMRC might be better when operational difficulties and economic conditions were considered.


INTRODUCTION
Neuroendocrine neoplasms are a group of heterogeneous tumors that frequently occur in the gastrointestinal tract, particularly in the rectum.The incidence of rectal neuroendocrine neoplasms (R-NENs) accounts for approximately 20% of the total gastrointestinal neuroendocrine neoplasms. 1This incidence is constantly updated as preventive screening for colon cancer has gained increasing interest. 2Although early-stage R-NENs are less malignant and indicate good prognosis, the prognosis of progressive R-NENs was found to be similar to that of adenocarcinomas. 3Therefore, early diagnosis and treatment are very important.
The treatment approach for R-NENs depends on their malignant potential.According to the 2012 European Association of Neuroendocrine Neoplasms, 4 endoscopic local excisional treatment is considered feasible for R-NENs ≤20 mm, well differentiated (G1-G2), and without lymphovascular involvement or invasion of the proper muscular layers.The pursuit of histologically effective resection has led to traditional polypectomy replaced with endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).Modified EMR (EMRM) and modified ESD (ESDM) were developed to balance between the safety and resection capability of EMR and ESD.In addition, transanal endoscopic microsurgery (TEM) is increasingly used as the initial treatment of R-NEN, previously used as a salvage procedure for incomplete clearance of R-NENs. 5However, there is no consensus on the most appropriate type of endoscopic intervention.Previous meta-analyses have assessed the efficacy and acceptability of ESD versus EMRM and ESD versus EMR. 6,7However, these analyses did not provide an adequate reference due to the limited interventions included.Network meta-analysis (NMA) could provide the highest evidence for treatment guidelines, 8 including a comparison of direct and indirect treatments, thereby providing more comprehensive recommendations for decision-making.
Particularly, exploring optimal endoscopic treatment modalities is important to increase the rate of early and effective treatments; improve patient survival; enhance the quality of patient care; and rationalize the use of healthcare resources.Therefore, this study compared the efficacy and acceptability of the existing endoscopic treatment modalities using an NMA to guide clinicians in developing optimal treatment strategies.

MATERIALS AND METHODS
This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension Statement for Network Meta-Analysis (PRISMA-NMA; Supplementary Table 1). 9The study protocol was registered in the Prospective Register of Systematic Reviews (PROSPERO CRD42023417278).

Search Strategy
Databases, including PubMed, Embase, Cochrane, CNKI, and Wanfang Data, were searched from January 2010 to March 2023 to retrieve relevant clinical studies.The following terms were used in combination (see Supplementary Table 2): "Rectal Neoplasms," "Neuroendocrine Tumors," "Carcinoid Tumor," "Endoscopic Mucosal Resection," and "Endoscopic Submucosal Dissection."Additionally, we manually searched the reference lists for relevant publications.No language or geographic restrictions were imposed.The filtered results were then imported into the Endnote Library (version ×9.3) for management.

Selection Criteria
To be eligible for this NMA, studies needed to meet the following criteria: First, adult patients underwent endoscopic therapies and were diagnosed with R-NENs after treatment.Second, endoscopic ultrasound or pathological examination suggested that R-NENs had low malignant potential (size ≤20 mm in diameter, well differentiation, no lymphovascular invasion, or invasion limited to mucosal or submucosal).Third, endoscopic techniques such as EMR, ESD, EMRM, ESDM, or TEM were included.Fourth, outcomes included histological complete resection (HCR).The main criteria for study exclusion were (i) duplicate publications, (ii) inaccessibility to original literature, (iii) non-clinical studies, and (iv) missing critical information to determine whether the inclusion criteria were met.

Literature Selection and Quality Assessment
To ensure data extraction's accuracy and research's rigor, 2 researchers (S.Z. and Q.C.) independently extracted, integrated, and cross-checked the data, while assessing the methodological quality of each included original study.The Newcastle Ottawa Scale was used to determine whether they were high quality (score 8 or 9), medium quality (score 6 or 7), or low quality (score ≤5). 10 Any disagreements regarding data extraction and quality assessment were resolved through discussion and judgment by a third investigator (B.Z.).

Outcomes
The goal of treatment was to achieve complete histological resection.Therefore, the primary outcome events

Main Points
• Regarding rectal neuroendocrine neoplasms ≤20 mm with low malignant potential, endoscopic submucosal dissection (ESD) outperformed endoscopic mucosal resection (EMR) in terms of resectability, whereas safety was a concern.Transanal endoscopic microsurgery (TEM) outperformed ESD in terms of resectability and safety, whereas surgery time and medical cost were concerns.Endoscopic submucosal dissection could be used as the primary treatment.However, TEM might be more effective if supported by economic conditions and hospital facility.

•
In regard to rectal neuroendocrine neoplasms ≤16 mm with low malignant potential, endoscopic mucosal resection with ligation (EMRL) combined the resectability by ESD with the safety of EMR with shorter operative time and lower cost than ESD.Endoscopic mucosal resection with ligation (EMRL) could be used as the primary treatment.

•
Considering rectal neuroendocrine neoplasms ≤10 mm with low malignant potential, EMRL, endoscopic mucosal resection with a cap (EMRC), and ESD showed better resectability and similar safety than did EMR, whereas EMRL and EMRC also demonstrated shorter time and lower cost than did ESD.EMRL, EMRC and ESD could be used as the primary treatment.However, EMRL and EMRC might be better when operational difficulties and economic conditions were taken into account.
included HCR, which represented no residual tumor tissue confirmed by pathological examination after endoscopic resection.Additionally, surgery time and complications (including procedure-related bleeding and perforation) have also been a focus of attention.

Statistical Analysis
Log odds ratios (OR) with a 95% confidence interval (CI) were used to compare binary outcomes.The mean difference (MD) and 95% CI were calculated for the continuous outcomes.The NMA was conducted using a random-effects Bayesian framework to predict the effects of all measures simply and straightforwardly. 11All direct and indirect evidence was combined to compare HCR, surgery time, and complication of various techniques for R-NENs.Subgroup analysis was performed, stratified by morphology (size ≤10 mm in diameter) and histology (low malignant potential confirmed by pathological examination).Meta-regression was performed to explore source of heterogeneity.The analysis was performed using the multinma package 12 and getmc package 13 in R (version 4.1.3).First, network diagrams were plotted to visualize the treatments compared directly or indirectly.Next, the log OR and MD of the pairwise comparisons were presented as league tables.The ranking probability of each measure was then calculated; a ranking curve was plotted.Heterogeneity among studies was assessed using the I 2 statistic.Moreover, the prediction intervals were displayed in a forest plot.In addition, potential inconsistencies between direct and indirect evidence were assessed using the deviance information criterion and node-splitting method.A funnel plot was created to assess the potential bias due to the small sample size, using symmetry as an evaluation criterion.

Assessment of Certainty of the Evidence
The final outcome reliability assessment of the NMA followed the guidelines of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group. 14The GRADE approach classifies the quality of evidence into 4 levels: high, moderate, low, and very low.For retrospective studies with an initial quality of evidence rated as "'low," it was downgraded if issues of study bias (with high risk), reporting bias, indirectness, heterogeneity, or inconsistency were identified.Conversely, evidence was upgraded if there was a large magnitude effect in each pair comparison.

Study Selection
Overall, 1430 literature records were obtained from databases and references (Figure 1).The techniques were ranked in the following order: first by EMR (SUCRA, 0.82), followed by EMRL (0.61), EMRP (0.56), and finally by ESD (0.01).In addition, pairwise comparisons across the 7 and 6 measures in the 2 subgroups revealed similar risks of complication.

Heterogeneity, Inconsistency, and Reporting Bias
There was no evidence of statistically significant global heterogeneity or global inconsistency regarding HCR, surgery time, or complication (Supplementary Table 5  and 6).However, partial local heterogeneity and inconsistency were found (Supplementary Figures 11-16 and Table 6).No significant reporting bias was found in HCR or complication.However, the main and subgroup analyses indicated significant bias in surgery time (Supplementary Figures 17-19).

Network Regression Analyses
Network regression was performed with en bloc resection rate, clarity of surgery time, clarity of complication, publication year to evaluate the effect of definition differences on outcomes, with patient's age, sex, and tumor location (distance from the anal verge) to evaluate the effect of patient and tumor conditions on outcomes.The influence of the above factors was not found (Supplementary Table 7).

Assessment of Evidence Certainty
Network meta-analysis included 74 mixed, 17 direct, and 116 indirect comparisons.In the GRADE assessment, 12, 132, and 63 comparisons were judged to have moderate, low, and very low certainty evidence, respectively (Supplementary Table 8).

DISCUSSION
Most rectal NENs manifest no carcinoid syndrome or typical clinical symptoms and are often discovered incidentally during routine colonoscopy.Therefore, with the popularization of colonoscopy, the incidence of rectal NENs is increasing every year. 2 Endoscopic treatment is currently the recommended modality for R-NENs with low malignant potential, including EMR, EMRM, ESD, ESDM, EFR, and TEM. 5 Recently, EMR is no longer used for treating R-NENs ≤20 mm due to its weak resectability.Endoscopic submucosal dissection requires prior delineation of a circumferential area around the lesion with an electrocauterization knife to enable submucosal resection to be performed under direct visualization for achieving a deeper and wider resection.Due to its high integrity and low risk of residue and recurrence, ESD is considered the standard excision technique for early-stage gastrointestinal tract cancers. 53This explains the results of a previous meta-analysis 7,54 and our NMA.Due to the large resection range of ESD, procedure-related bleeding and perforation were usually more likely to occur compared to EMR. 55 However, there is still controversy over the risk of complications for smaller R-NENs.Yong et al 7 suggested that the bleeding risk of ESD for R-NENs between 10-20 mm was concerning, whereas the bleeding risk of ESD for R-NENs ≤10mm was acceptable as EMR.Zhou et al 54 revealed that for R-NENs ≤15mm with low malignant potential, the risk of complications of ESD was similar to that of EMR.Regarding R-NENs ≤20 mm with endoscopically suspected low malignant potential, the risk of complications between ESD and EMR remains uncertain.Considering R-NENs ≤20 mm with pathologically confirmed low malignant potential or R-NENs ≤10 mm with endoscopically suspected low malignant potential, our study indicated that the risk of complications was similar between ESD and EMR.These results emphasized the importance of improving the accuracy of preoperative diagnosis of R-NENs.ESD was often associated with higher medical expenditures compared to EMR due to higher treatment costs and longer hospital stays.Although it was not possible to analyze the cost-effectiveness of ESD due to the significant differences in healthcare costs between countries and regions, confirmed by several studies 16,29 and clinical realities.In addition, popularizing ESD due to operational difficulty and instrument requirement is still difficult.
To overcome the limitations of EMR and ESD, various EMRMs have been developed.However, the most suitable technique for treating R-NENs with low malignant potential remains unknown.In earlier meta-analyses, EMRMs were usually compared to EMR or ESD, considered as a whole. 6,54However, there was no comprehensive comparison between each EMRM.This makes it difficult for inexperienced endoscopists to make sensible decisions in practice because there are still variations in their methodology and application.Therefore, we derived different recommendation levels for different techniques by comparing each EMRM to EMR and ESD separately and analyzing them with the effect rankings.
EMRL uses ligation-assisted instruments, such as bands or clips, to sufficiently lift the tumor tissue, allowing for resecting lesions deeper in the submucosa compared to conventional EMR. 41This is consistent with our findings.Due to the ongoing controversy about EMRMs over the treatment of R-NENs between 10-20 mm, 56 the maximum tumor diameter in the original studies on EMRL in this NMA is only up to 16 mm.Therefore, we suggest that EMRL might outperform EMR regarding resectability of R-NENs ≤16 mm with low malignant potential.In addition, Lim et al. 38 indicated that EMRL had a wider resection range than did ESD to achieve a higher HCR rate for R-NENs ≤10 mm.Although the difference between EMRL and ESD is not statistically significant, EMRL ranks higher in HCR rate than does ESD.EMRC uses negative pressure to aspirate an elevated lesion into a transparent cap before resecting it, providing similar resectability and safety to ESD but with a shorter duration. 37However, due to the transparent cap's poor freedom and limited volume, EMRC may be more suitable for smaller tumor compared to ESD.Consistent with most studies, 27,41 our study revealed that EMRC could be more suitable for the treatment of R-NENs ≤10mm.When tumor size is appropriate, EMRC can even achieve a resection effect that is not inferior to EMRL.EMRP involves injecting saline into the submucosa using an injection needle to augment the lesion and create a circumferential incision (pre-incision) using the tip of a loop or special endoscopic cutter, and removing the tumor with the loop.The advantage of EMRP over other EMRMs is that there is no limitation on the size of the resected tumor. 26EMRD uses a dual-channel endoscope to lift the lesion with forceps and snare it. 15However, dual-channel endoscopy is not widely used.EMRU achieves deeper lesion resection by filling the intestinal cavity with water. 43Although studies have shown that EMRP, EMRD and EMRU could replace ESD for treating R-NENs ≤10mm or 15mm, 22,28 we found that the therapeutic benefit of them was not superior to that of EMR.Therefore, caution should be exercised when selecting EMRP, EMRC, or EMRU.Regarding surgery time, EMRL and EMRC might cost less compared to ESD for R-NENs ≤16mm with low malignant potential, while EMRU might cost less compared to ESD for R-NENs ≤10mm with low malignant potential.Regarding complication risk, we considered that each EMRMs might be relatively similar to EMR.
This study included 2 modified ESD procedures: C-type ESD 52 (replacing the pre-delineated circumferential area with a C-shaped area) and dental floss traction-assisted ESD. 39Our results revealed that these modified techniques could improve the performance of ESD in terms of both resectability and safety.ESDMs would be good endoscopic treatments if were technically feasible due to their better therapeutic efficacy and similar safety compared to EMRMs.Although the quality of evidence suggesting that the insignificant difference between ESDM and ESD in surgery time was very low, ESDM is a modified technique of ESD.Therefore, we suggest that the difference in surgery time between them should not be significant, which is consistent with the views of the studies we included. 39,52TEM, which combines the advantages of traditional transanal rectal surgery and laparoscopic surgery, can be easily used for resecting R-NENs and salvage treatment. 24Our findings indicated that TEM likely outperformed ESD in terms of resectability and safety for R-NENs ≤20 mm with endoscopically suspected low malignant potential.However, since TEM is more technically and equipment-demanding compared to ESD, resulting in longer procedure times and hospital stays and higher medical expenditures, 57 the endoscopists should pay careful attention to the above issues.
This study has several limitations: First, because there are too few prospective randomized studies comparing endoscopic techniques, the inherent selection bias of retrospective studies included in this NMA might be inevitable .Second, although we conducted subgroup analysis and regression analysis of various confounding factors, there are still some significant local heterogeneity and inconsistency, which may be due to the inherent limitations of methodology of NMA.Therefore, we critically assessed the quality of evidence, which readers may apply with caution given the results and quality of evidence.Third, since R-NENs are prevalent in Asian populations, most of the published articles now originate from Asia, 2 and the analysis based on this data may have limited generalizability to other populations.Last, the present study is limited to exploring the surgery time and medical cost for various endoscopic technique due to the significant differences in different countries or region.In conclusion, more high-quality randomized controlled studies need to be conducted in to address these limitations.
Regarding R-NENs ≤20 mm with low malignant potential, ESD could outperform EMR in terms of resectability, whereas safety remains a concern.Identify the report as a systematic review incorporating a network meta-analysis (or related form of meta-analysis).

Structured summary 2
Provide a structured summary including, as applicable: • Background: main objectives; • Methods: data sources; study eligibility criteria, participants, andinterventions; study appraisal and synthesis methods, such as network meta-analysis.• Results: number of studies and participants identified; summary estimates with corresponding confidence/credible intervals; treatment rankings may also be discussed.
Authors may choose to summarize pairwise comparisons against a chosen treatment included in their analyses for brevity.• Discu ssion /Conc lusio ns: limitations; conclusions and implications of findings.
• Other: primary source of funding; systematic review registration number with registry name.

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.Clearly describe eligible treatments included in the treatment network, and note whether any have been clustered or merged into the same node (with justification).
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Study selection 9
State the process for selecting studies involved screening, eligibility, and determining which studies would be included in the meta-analysis).
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.
Data items 11 List and define all variables for the research project or study.3. Assumptions: Any underlying beliefs or suppositions that were made during the data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Geometry of the network
S1 Describe methods used to explore the geometry of the treatment network under study and potential biases related to it.This should include how the evidence base has been graphically summarized for presentation, and what characteristics were compiled and used to describe the evidence base to readers.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. (Continued)

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Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means).Also, describe the use of additional summary measures assessed, such as treatment rankings and surface under the cumulative ranking curve (SUCRA) values, as well as modified approaches used to present summary findings from meta-analyses Synthesis of results 14 Describe the methods of handling data and combining results of studies for each network meta-analysis.This should include, but not be limited to: • Handling of multi-arm trials; • Selection of variance structure; • Selection of prior distributions in Bayesian analyses; and • Assessment of model fit.

Assessment Of Inconsistency
S2 Describe the statistical methods used to evaluate the agreement of direct and indirect evidence in the treatment network(s) studied.Describe efforts taken to address its presence when found.

Risk of bias across studies
15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).
Additional analyses 16 Describe methods of additional analyses, if done, indicating which were pre-specified.This may include, but not be limited to, the following: • Sensitivity or subgroup analyses; • Meta-regression analyses; • Alternative formulations of the treatment network; and • Use of alternative prior distributions for Bayesian analyses (if applicable).

Study selection
17 Give numbers of studies were screened, assessed for eligibility, and included in the review.
The reasons for exclusions at each stage were as follows, ideally with a flow diagram.

Results of individual studies
20 For all outcomes considered (benefits or harms), present, for each study: 1) simple summary data for each intervention group, and 2) effect estimates and confidence/credible intervals.Modified approaches may be needed to deal with information from larger networks.

Synthesis of results
21 Present results of each meta-analysis done, including confidence/credible intervals.In larger networks, authors may focus on comparisons versus a particular comparator (e.g., placebo or standard care), with full findings presented in an appendix.League tables and forest plots may be considered to summarize pairwise comparisons.If additional summary measures were explored (such as treatment rankings), these should also be presented.The Newcastle Ottawa Scale (NOS) was used to determine whether original studies were high quality (score 8 or 9), medium quality (score 6 or 7), or low quality (score 5).
Information About the Outcome Events in Studies (Completed )

Figure 2 .
Figure 2. Network diagrams of various comparisons.(A) Comparisons on endoscopic methods for HCR.(B) Comparisons on endoscopic methods for surgery time and complication.Each circular node represents a type of treatment.The node size decreases equally based on the order of sample size receiving treatment (in brackets).Each line represents a type of head-to-head comparison.The width of the lines is proportional to the number of trials comparing the connected treatments.EMR, endoscopic mucosal resection; EMRC, endoscopic mucosal resection with cap; EMRD, endoscopic mucosal resection with dual-channel endoscope; EMRL, endoscopic mucosal resection with ligation; EMRP, endoscopic mucosal resection with pre-cutting; EMRU, endoscopic mucosal resection under water; ESD, endoscopic submucosal dissection; ESDM, modified endoscopic submucosal dissection; HCR, histological complete resection; TEM, transanal endoscopic microsurgery.

Figure 4 .
Figure 4. Ranking curves of the network meta-analysis.The figure shows each outcome in different colors.The horizontal axis displays rankings ranging from 1 to 7. The vertical axis shows the probability of being ranked in any specific position, from 0 to 1. EMR, endoscopic mucosal resection; EMRC, endoscopic mucosal resection with cap; EMRD, endoscopic mucosal resection with a dual-channel endoscope; EMRL, endoscopic mucosal resection with ligation; EMRP, endoscopic mucosal resection with pre-cutting; EMRU, endoscopic mucosal resection under water; ESD, endoscopic submucosal dissection; ESDM, modified endoscopic submucosal dissection; TEM, transanal endoscopic microsurgery.
for the review in the context of what is already known, including mention of why a network meta-analysis has been conducted.Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).
Some concerns No concerns No concerns Major concerns No concerns Very low Some concerns No concerns No concerns Major concerns No concerns Low 12 Some concerns No concerns No concerns Major concerns No concerns Low 12 represent the risk of bias (green: No concerns or Low risk or High confidence, blue: Moderate confidence, yellow: Some concerns or Low confidence, red: Major concerns or Very low confidence).1 Confidence in evidence was downgraded for significant heterogeneity. 2 Confidence in evidence was upgraded for large magnitude effect (OR >2 or MD >0). 3 Confidence in evidence was downgraded for high risk study bias.4 Confidence in evidence was downgraded for reporting bias.

Table 1 .
Baseline Characteristics of Studies Included in the Network Meta-Analysis

Table 1 .
Checklist of the PRISMA Extension for Network Meta-analysis (Continued) Additional analysis23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, metaregression, alternative network geometries studied, alternative choice of prior distributions for Bayesian analyses, and so forth [see Item 16]).